Oral therapeutic composition and process of preparation



United States Patent ORAL THERAPEUTIC COMPOSITION 'AND PROCESS PREPARATION 'Ma'rshall E. Bennett, New York, N. Y'.,-assignor to The Upjohn Company,- Kalamazoo, ofMichigan No'Dr'awing. Application Eebiuai i 9; 1954 Serial No. 409,261

11 Claims. Grim-51.5

Mich., a corporation This invention relates to therapeutic com ositions and to a process fortheir preparation. More particularly, it relates" tofluidstabl'e suspensionswhich are rimarily intended for oral use in the treatment of gastro-intestinal I V disorders which" are either of an infectious origin or have actual or" potential infectious complications, and to a proeessror the preparation of suchcompositions.

' Gastro-intestinal'disorder's' having" infectious complications are among the more common afllictionsfofflall animals, including the human race. Among the more dis-- conifor'ting'symptomsofrsuch disorders are fever, loss 2,828,242 Ratented Mar- 25, 1958 an" aqueousv vehicle. Neomycin may be. used' in 7 free form, or inthe form of one of its therapeutically active salts, such as thesulfate. As the word neomycin is a used in the present specification, it includes not only the free-base butalso the therapeutically active salts thereof. The-wordisfalsoused in thesame broad sense as in Walt-s man on Neomycin,.Rutgers University Press, New Brunswick, New-Je-rsey. (1-953). It includes forms B and C and mix turesofiB and C. Methylcellulose is included in the composition-ioprevent or inhibit settling, to act as a suspending agent. giving longer suspension qualities, and to prevent-solid gelling or excessive thickening. Without methylcellulose and the addition of neomycin to the aqueous 7 vehicle. before adding bentonite and pectin settling occurs. in; amatter. of weeks, as compared with abouhone year-toreachapproximately the same degree of settling:withmethylcellulose in the composition. About one to threepercent methylcellulose is considered operative for this purpose, with two percent being preferred.

0 The viscosity of methylcellulose, measured in centipoise units, is important,-.though.not critical, to the present invention..-- The preferred viscosity will vary with the amounts, of'neornycin, bentonite and pectin used, all of which canbe varied considerably.

Kaolins may befuse'd along withthe bentonite'in the of a petite, vomiting, diarrhea an'd'irritation of the gastro-- intestinal membranes. Several therapeutic agents are 'known to counteract such symptoms, forexample, varidisorder, i; e., infection.

ous combinations of kaolins, bentonite and pectin. These therapeutic agents tend to alleviate some of thesymptoms of the disorder by adsorbing toxins, reducingdiarrhea; and soothingirritated membranes of'the gastro-intestinal tract. They may, however, have little effect upon what may be the primary' cause or' aserious complication ofthe Neomycin is one of the w more compositions for their" therapeutic value in adsorbing toxins. The properties of both the kaolinsand bentonite are responsible for the adsorption of toxins. Since methylcellulose tends to reduce surface tensiomananti-foam agent such as Tween 85 (polyoxyethylene,sorbitan trire'cently developed antibiotics which has achieved'recog-- nition for itsusefulness in such gastro-intestinal disorders where infection is a'factor;

Pr'or to'the present invention thecombi'nation of neomycin with bentoniteancl pectin had never been accomplished nor had the beneficial res'ultsact'u'all'y' obti il' ed thereby been appreciated. The present inventionis a 7 result of the solution of special'problems which arose in the attempt to produce such a preparation. ,7 g a It is therefore one of the principal objects of the present invention to provide thereapeutic compositions which i are etfective in the treatment of gastro-intestinal disorders" having either an infectious origin or actuator potential infectious complications; Another object of the present invention is to provide such compositions'in which there is little or no interference or hartnful .reaction' between. the active ingredients thereof. Stillanother objectisto providesuch compositions which form fluid, stable suspensions for oral use in humans and animals." Still a'nother object is to provide a process for the preparation of 'siichficor'npositions which for practicalpurpose's'prevents or mrmniizes' reactionsin or other interferences with'the preparation thereof. Other objects of this inventionwill be apparent to those skilled in the art to which the invention pertains.

The ,forlegoing and additional objects have been ac:

complish'ed by the provision of a novel composition comprising neomycin, bentonite, pectin andimethylce'll ul'ose and a novel process for the preparation of sucha cornposition".

:The' essential'a'ctive ingredients of the novel co n'ipo'sitions of the present invention are neomycin, bentonite, and pectin. The'composition is preferably suspended in a vehicle suitable for oral administration. The only limita'tions' on the vehicle or diluent used are compatability with the active ingredients and suitability-tor oleate), is preferably added to thecomposition:

, In attempting to add neomycin to'a prepared'composition containing bentonite and pectin, it was discovered that the composition thickened and became so viscous that it could not readlly'be poured from a bottle. Although the mechanism of action is not clearly understood, it is believed that the positivelych'arged' neomycin ion is reactive with negatively charged'complex'materials, such as pectic acid and bentonite present in the composition. However, it was*unexpectedly'discovered that this difiiculty is avoided by changing the order-of addition of 'ingredients to the-completed composition; When the -dr-y powders-of bentonite and pectin areaddedto. asolution .of neomycin sulfate, the tendency: to: thicken is largely avoided.

'Atthat point new problems developed: settlingj and 'packingoccur after the product is allowed t'o st'and on' the ljshelffor a relativelyshort periodiofi time," making. the

product ditficult to"resuspend-;by shaking, Several suspending agents were tried inan attempt to; solve these problems.

In the course ;of these. experiments it was unexpectedly discovered .thatvmethylc'ellulose not'only reduces the thickening produced by the additionofzneomyci'n but also isjthe best ofthe suspending agentsused.

. However, the order of. mixing is still critical but methylquire m'ents' of the. ingredients such as bentonite, pectin human-use. The combination is preferably preparedin and kaolin on the one hand, and the neomycin and other possibleantibacterial agentson' the other. When neornycin is the only antibacterial agent present, a pH'range between about 3".0'an'd 6;0 is operative with a range between 4.0and 4.7 being'preferred. The work of otlie'rs (Schoe'nhard' et' al-., Antibiotics and Chemotherapy3 -'41 I (1953)) indicates that an acid pH is detrimental to the activity of neomycin. Surprisingly when formulated in the present composition neomycin has proven stable, and its antibiotic properties have remainedunimpaired.

The amount of neomycin used in a composition such as that shown in Example lis between about 0.065- gram per fluid ounce to about 1.2 grams per fluid ounce, 0.25

with citric acid. Assay indicated that the neomycin in to 0.5 gram being preferred. A concentration below about 0.065 gram per fluid ounce can be-preparcd but is generally considered to be below the therapeutically effective level of neomycin. A concentration greater than 1.2 grams per fluid ounce is operative but has a tendency toward greater settling. The amount of neomycin used, however, is not considered critical to the present invention since it varies with such factors as the amounts of the other materials used and the viscosity of methylcellulose.

Other antibacterial agents, such as the insoluble paminobenzenesulfonamides, and penicillin, or their therapeutically active insoluble salts and derivatives, although not critical to the present invention, can also be included in the novel. compositions of the present invention Whenever it is believed to be of value to utilize the combined antibacterial properties of the added materials and neomycin. Illustrative relatively insoluble sulfonamides include sulfadiazine, sulfamerazine, phthalylsulfathiazole, succinylsulfathiazole, sulfathiazole and sulfaguanidine.

Various other inert ingredients can also be present in EXAMPLE 1 One embodiment of the present invention can be illustrated by the following formulation showing the contents of 500 gallons:

Formula for 500 gallons Ingredients Gals. Lbs. Ozs Grs.

Methylparaben, U. S. P- 8 6 Saccharin Soluble Gram, U. S. P 1 13 '148 Citric Acid Po., U. S. P I .3 15 Tween 85 2 1 167 Deionized water .320 Kaolin, F p 822 Pectin, N. F 18 4 Bentonlte Powder, U. S. P 82 8 Methylcellulose, N. F., 25 cps. mi-

cronized 83 10 Neomyein Sulfate Powder. 45 12 Deionized water (add sutficient to make up desired amount) 500 Citric Acid Powder, U. S. P. (to adjust pH) p A 500 gallon lot of the foregoing composition can be prepared in the following manner which also illustrates the novel process of the present invention: methylparaben, saccharin, citric acid and Tween No. 85 are dissolved in approximately 320 gallons of deionized water. Kaolin, methylcellulose 25 cps. (centipoise units), pectin and bentonite are weighed .into a mixer and mixedfor 25 minutes. The kaolin methyl cellulose pectin bentonite mixture is added to the water solution at such a rate as to wet the powders in a one hour period. The whole is mixed thoroughly and enough deionized water is added to make up volume to 490 gallons. This is mixed for a minimum of fifteen hours. Neomycin sulfate is dissolved in five gallons of deionized water and added to the foregoing. Enough" deionized water is added to make up volume to 500 gallons. The whole is mixed thoroughly. The pH is adjusted to between 4.0 and 4.7

the composition was both stable and potent. Clinical success for the composition is reported in Waksman on Neomycin, Rutgers University Press, New Brunswick, N. J. (1953), p.167.

EXAMPLE 2 To a 500 gallon lot of the composition such as that.

shown in Example 1, 105 pounds and113 ounces each of s'ulfadiazine and sulfamerazine as micronized powders are added to form a composition having the combined antibacterial properties of neomycin and the sulfonamides. This provides a composition containing 0.75 gram per fluid ounce of each of the added sulfonamides, i; e.,' sulfadiazine and sulfamerazine. I

In place of the combined sulfonamides used above, any one of sulfaguanidine, sulfathiazole, phthalylsulfathiazole, or succinylsulfathiazole can be added in suflicient quantity to make up 1.5 grams per fluid ounce, or

' 105 pounds and ten-ounces for each 500 gallon lot.

' -Itis to be understood that the invention is not to be limited to the exact details of operation and exact compositions shown and described as obvious modifications and equivalents will be apparent to one skilled in the art,

, and the. invention is therefore only to be limited by the scope of the appended claims.

I claim:

' 11 A therapeutic composition comprising neomycin,

bentonite, pectin and methylcelluloseas a fluid, stable suspension.

4. An oral therapeutic composition, adjusted to a pH 0 between about 3.0 and 6.0, comprising neomycin, bentonite, kaolin, pectin, methylcellulose and a liquid oral diluent.

,an aqueous vehicle containing bentonite, pectin and methylcellulose.

7 7. The process for the preparation of an oral therapeutic composition which "comprises. adding neomycin sulfate to an aqueous vehicle containing bentonite, pectin and methylcellulose.

8. The process for the preparation of an'oral therapeutic composition which comprises adding neomycin sulfateYto an aqueous vehicle containing completely swelled V bentonite, kaoljn, completely swelled pectin and methyl-.

' cellulose. I

19. The I process which comprises preparing a fluid aqueous suspension of bentonite and pectin with methylcellulose and thereafter incorporating neomycin into said 1.2 grarns per fluid ounce. v 10. The process of preparing g a fluid suspension in the proportion of between about 0.065 and suspension of aqueous vehicle which comprises preparing a fluid suspension containing at least completely swelled bentonite,

completely swelled pectin, and methylcellulose, incorpo- .;rating the neomycin therein in an amount suflicient to provide between about 0.065 and 1.2 grams per fluid 7 ounce, and adjusting the :pH to between about 3.0 and 6.0.

' 11, The processof preparing a fluid stable suspension of bentonite, pectin, methylcellulose, and neomycin sulfate in' an aqueous vehicle which comprises preparing ian 'aqueousfvehicle containing atileast bentonite, pectin,

and methylcellulose, incorporating the neomyciu sulfate therein in an amount sufficient to provide between about 0.065 and 0.5 gram per fluid ounce and adjusting the pH to between about 4.0 and 4.7.

References Cited in the file of this patent FOREIGN PATENTS Germany Jan. 8, 1953 Great Britain Mar. 26, 1952 6 OTHER REFERENCES 

5. A THERAPEUTIC COMPOSITION COMPRISING NEOMYCIN, BENTONITE, PECTIN, METHYLCELLULOSE AND A MEMBER SELECTED FROM THE GROUP CONSISTING OF SULFADIAZINE, SULFAMERAZINE, SULFAGUANIDINE, PHTHALYLSULFANTHIAZOLE AND SUCCINYLSULFATHIAZOLE IN AN AQUEOUS VEHICLE SUITABLE FOR ORAL USE. 